Although previous findings on Abeta42 vaccination in transgenic (Tg) mice are very promising, this approach may not be feasible for humans due to potential toxicity. Several studies have shown that Abeta42 forms toxic fibrils that are a major component of the plaques within the AD brain, and it crosses the blood brain barrier (BBB) in experimental animals. Hence, in humans the injected Abeta42 may enter the brain and co-deposit on existing plaques or even initiate deposit formation, thereby leading to increased brain damage and subsequent memory loss. Instead of using toxic fibrils of Abeta42, we have vaccinated AD-like Tg mice with an Abeta homologous peptide which is not toxic and does not form fibrils, but activates the immune system and leads to 89% clearance of Abeta plaques. Because its sequence is not identical to human Abeta, it is less likely to lead to autoimmunity. The effect of peptides with similar properties, and that of adjuvants approved for human use, will be assessed. Antibodies to non-fibrillar derivatives may have higher affinity for soluble Abeta than those generated against fibrillar Abeta. The resulting antibody-mediated clearance of soluble Abeta from peripheral tissues may lead to an efflux of Abeta from the CNS, and this peripheral mode of action may have fewer CNS side effects. There are no reports on the integrity of the BBB in Tg APP mice. In preparation for human studies, it is imperative to determine if antibody penetrance through the BBB in these Tg mice is abnormally high. AD-like behavioral impairments have been observed in these mice, and we will examine if our immunization will lead to cognitive improvements. Overall, this approach has a much lower risk of toxic effects in humans, while maintaining the therapeutic potential of vaccination for AD. As importantly, the feasibility of vaccination for neurofibrillary tangles will be explored in Tg mice that model FTDP-17. The use of phosphorylated peptide epitope as antigen and monoclonal antibodies that specifically recognize abnormal tau proteins should reduce the likelihood of autoimmunity. Elimination of the most accessible target, the extracellular tangles, may diminish associated pathology. Furthermore, because of numerous reports of cellular uptake of antibodies, intracellular tangles may also be affected, leading to reduced neuronal loss and thereby slowing of cognitive deterioration.